These studies are directed to elucidating the molecular defects that underly the following human hereditary disorders of connective tissue: Marfan's syndrome, Ehlers-Danlos' syndrome, osteogenesis imperfecta, and homocystinuria. Collagen synthesized in culture by fibroblasts from affected individuals will be analyzed for defects in intra-and intermolecular cross-linking. The individual alpha chains of the collagen molecule will be cleaved to smaller peptides, and the chemical structure of the isolated cross-linking regions examined in detail. Precursor forms of collagen synthesized by these fibroblasts will also be studied with respect to structure and enzymatic processing to native tropocollagen.